Conversion of 5-(chloromethyl)-2-furaldehyde into 5-methyl-2-furoic acid and derivatives thereof

ABSTRACT

The present invention concerns the synthesis of 5-methyl-2-furoic acid, including ester, amide, and thioester derivatives of such from 5-(chloromethyl)-2-furaldehyde (CMF). The molecules so prepared are useful as intermediates for pharmaceutical, food, and fragrance molecules; as well as fuel or fuel additives.

TECHNICAL FIELD

The present invention concerns the synthesis of 5-methyl-2-furoic acid,including ester, amide, and thioester derivatives of such from5-(chloromethyl)-2-furaldehyde (CMF). The molecules so prepared areuseful as intermediates for pharmaceutical, food, and fragrancemolecules; as well as fuel or fuel additives.

BACKGROUND ART

The generation of commodity chemicals from renewable feedstocks remainsas one of the top priorities in the field of green chemistry. Inaddition, chemical processes that can operate in a catalytic fashion,such that toxic stoichiometric by-products can be avoided, will beessential in developing long-term, sustainable routes for molecules ofinterest. Though most catalytic processes in use today are mediatedthrough the action of transition metals, recent advances have shown thatcertain all-organic scaffolds, i.e. containing only non-metal atoms suchas carbon, hydrogen, nitrogen, sulfur, oxygen, or phosphorus, can act ina catalytic fashion and affect seemingly non-obvious transformations onreactive substrates.

One such scaffold that is capable of unusual transformations compriseheterocyclic rings in which three consecutive atoms in the ring are ofthe form ‘X⁺=C⁻−X’, with ‘X’ being nitrogen, sulfur, silicon, orphosphorus (FIG. 2). Upon treatment with a suitable base, thesemolecules generate stabilized, singlet carbenes, containing a divalentcarbon center. These carbenes are capable of imparting very unusualreactivity on certain organic functional groups; the most wellunderstood being that of the vitamin Thiamine on pyruvate duringmetabolism. Much of the current academic research on these carbenesfocuses on the grouping ‘R(R′)N⁺=C−⁻XR″’, which have been termed‘N-heterocyclic carbenes (NHC)’, and their action on aldehydes.Classically, aldehyde groups are considered to be highly reactiveelectrophiles, with a partial positive charge residing on the carbonatom. NHC organocatalysis is capable of reversing this charge, in aphenomenon known as ‘umpolong’ reactivity, wherein that same carbon nowbears a partial negative charge in the aldehyde-NHC adduct (See SeebachAngewandte Chemie International Edition in English 18, 239 (1979)). Thechemical literature contains examples of additions, eliminations,cycloadditions, and many other reactions where this intermediate isinvoked.

Recent publications from Mark Mascal at the University of California,Davis, detailed a high yielding process from which5-(chloromethyl)-2-furaldehyde (CMF) can be produced from a number ofrenewable cellulosic and hemicellulosic feedstocks (See Mascal andNikitin Energy & Fuels 24, 2170 (2009)). As the process makes use ofstrong mineral acids, it is agnostic to stereochemistry and glycosidiclinkages of the unit saccharides, and will convert six-carbon sugars toCMF, with the exception of deoxy sugars or gluconuric acids. Similarwork in the field of furans-from-carbohydrates has focused on thegeneration of 5-(hydroxymethyl)-2-furaldehyde (HMF) (See Binder andRaines Energy & Environmental Science 3, 677 (2010)). Both CMF and HMFcan be converted to valuable chemicals, primarily through catalytichydrogenation to afford 5-methyl-2-furaldehyde or 2,5-dimethylfuran, orelse oxidized to 2,5-furan-dicarboxylate, which can be used as a plasticmonomer.

Of particular relevance to the present invention is the conversion ofCMF to 5-(ethoxymethyl)-2-furaldehyde (EMF) by Mascal (See Nikitin andMascal Angewandte Chemie International Edition 47, 47 (2008)), which hasdemonstrated favorable fuel characteristics in terms of its energycontent (30.3 MJL-1). Though similar to gasoline in this regard, EMFfailed to blend with gasoline at an appreciable level, and is also proneto auto-oxidation upon extended standing by virtue of the reactivealdehyde group (FIG. 3).

α-chloro-aldehydes are substrates that have been studied by Bode, Rovis,and Scheidt with NHC catalysis (See Sohn and Bode Organic Letters 7,3873 (2005)); Reynolds and Rovis Journal of the American ChemicalSociety 127, 16406 (2005)); Chan and Scheidt Organic Letters 7, 905(2005)). Mechanistically, after addition of the carbene to the aldehyde,the negative charge at the aldehyde-carbon center will eliminatechloride, affording an enol intermediate (FIG. 4). After tautomerizationto the ketone, exogenous nucleophiles, such as alcohols, water, oramines, will expel the azolium moiety and regenerate the catalyticcycle. The resultant acid, ester, or amide, respectively, is immune fromfurther reaction with the catalyst. CMF can be considered as aα-chloro-aldehyde, however the carbon-chlorine σ-bond is separated fromthe aldehyde π-bond by the furan ring system. In functional groupswherein a π-bond or π-system connects certain atoms, the group can beconsidered as ‘vinylogous,’ ‘doubly-vinylogous,’ etc. For example, anamide functional group with a carbon-carbon double bond connecting thenitrogen to the carbonyl is called a ‘vinylogous amide.’ In the case ofCMF, the carbon-chlorine group and the aldehyde are ‘doubly-vinylogous,’or perhaps, ‘furanylogous,’ where the furan π-system connects the bonds,and thus preserves the reactivity.

The present invention describes the high yielding conversion of CMF andrelated derivatives of 5-methyl-2-furaldehyde to 5-methyl-2-furoic acidand derivatives thereof using this novel transformation, catalyzed byNHC molecules. CMF, which is produced from renewable carbohydratefeedstocks, can be converted to useful products in a catalytic manner,without using transition metals, pressurized hydrogen gas, or extremesof pressure or temperature.

DESCRIPTION OF INVENTION

In one embodiment, the present invention provides a method for preparingmethyl 5-methyl-2-furoate ester, in greater than 50% yield. The methodincludes contacting a furan-containing molecule of formula II, a base,an organic solvent, a catalyst, and methanol, at 32° C., such thatmethyl 5-methyl-2-furoate ester is produced.

In another embodiment, the present invention provides a method forpreparing ethyl 5-methyl-2-furoate ester, in greater than 50% yield. Themethod includes contacting a furan-containing molecule of formula II, abase, an organic solvent, a catalyst, and ethanol, at 32° C., such thatethyl 5-methyl-2-furoate ester is produced.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates molecules of formula I and formula II, which are theproducts and substrates, respectively, for the present invention.

FIG. 2 illustrates the divergent reactivity of5-(chloromethyl)-2-furaldehyde (CMF, 1) to either5-(ethoxymethyl)-2-furaldehyde (EMF, 2) or ethyl 5-methyl-2-furoate (3)depending on the absence or presence of catalyst.

FIG. 3 illustrates the proposed catalytic cycle mechanism of the presentinvention, along with that of known α-chloroaldehydes with NHCcatalysis.

FIG. 4 illustrates representative precursor salts of N-heterocycliccarbene catalysts, and their deprotonation with bases.

FIG. 5 is a schematic illustration of the reduction of glycerol to1,2-propanediol, or dehydration to acrolein.

FIG. 6 is a schematic illustration of thiazolium or triazolium ringsystems as nucleophilic agents.

FIG. 7 is a schematic illustration of an example method according to thepresent invention.

FIG. 8 is a schematic illustration of an example method according to thepresent invention.

FIG. 9 is a schematic illustration of glucose and derived molecules.

FIG. 10 is a schematic illustration of chloroaldehyde attacked by thethiazolium ring, followed by elimination of the chloride.Tautomerization to the ketone provides an intermediate which issusceptible to hydrolysis.

FIG. 11 is a schematic illustration of disparate reactivity of the acylintermediate to provide furoate esters.

MODES FOR CARRYING OUT THE INVENTION AND INDUSTRIAL APPLICABILITY

I. General

A method according to the present invention comprises preparing5-methyl-2-furoic acid, including ester, amide and thioester derivativesfrom CMF, as useful chemical building blocks and fuel or fuel additives.The first step involves contacting a molecule of formula II, thecatalyst, a base, an organic solvent and a reactive nucleophile, attemperatures between 10 degree C. and 50 degree C. The reaction isquenched with water, and hydrophobic furan product may be extracted witha hydrophobic solvent and purified by silica chromatography. Thehydrophobic furan products may also be isolated by distillation,precipitation, or sublimation. The yield to methyl 5-methyl-2-furoateand ethyl 5-methyl-2-furoate are greater than 50% by this method. In thecase of hydrophilic furan products, such as 5-methyl-2-furoic acid, theproduct may be purified by distillation, precipitation or sublimation.

II. Definitions

As used herein, the term “catalyst” refers to any atom or grouping ofmolecules that is present in sub-stoichiometric amounts with respect tothe CMF, which is able to affect the desired chemical transformation to5-methyl-2-furoic acid, and esters, amides, and thioesters thereof. Thecatalyst may also be present in equal or super-stoichiometric quantitieswith respect to CMF.

As used herein, the term “N-heterocyclic carbene” refers to anypolycyclic or heterocyclic organic molecules, which contains at leasttwo non-carbon atoms, which include one nitrogen, and one from thefollowing: nitrogen, sulfur, phosphorus, or silicon; as well as at leastone carbon atom. These atoms are arranged in such a way that upontreatment with an anhydrous base, a singlet carbene will form on acarbon atom contained within the heterocyclic ring.

As used herein, the term “nucleophile” refers to organic molecules thatcontain a reactive electronegative element. Examples include water;alcohols, including methanol, ethanol, butanol, propanol, and otheraliphatic or aromatic groups; amines, including ammonia, alkyl ammonia,dialkyl ammonia, and trialkylammonia groups; and thiols, includinghydrogen sulfide, and alkyl mercaptan species; and metal-stabilizedcarbon anions, such as alkyl-magnesium or alkyl-lithium species.

As used herein, the term “base” refers to molecules capable ofneutralizing acidic species. Bases useful in the current inventioninclude, but are not limited to, potassium carbonate, cesium carbonate,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), and quinuclidine. Other bases are also useful, such sodiumcarbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate,alkyl amines, dialkylamines, and trialkyl amines.

As used herein, the term “singlet carbene” refers to a carbon atombonded to two substituents, with the remaining atomic orbital geometrycomprising an s-orbital bearing two electrons, and an empty p-orbital.

As used herein, the term “organic solvent” refers to solvents which aregenerally non-polar, polar aprotic, or polar protic solvents. Organicsolvents include, but are not limited to, tetrahydrofuran, acetonitrile,diethyl ether, methyl t-butyl ether, ethyl acetate, pentane, hexane,heptane, cyclohexane, benzene, toluene, methanol, ethanol, as well ashalogenated solvents such as chloroform, dichloromethane, carbontetrachloride, 1,2-dichloroethane, or combinations thereof. Otherorganic solvents are useful in the present invention.

As used herein, the term “hydrophobic solvent” refers to solvents whichare immiscible with water. Extraction solvents include, but are notlimited to, diethyl ether, ethyl acetate, methyl t-butyl ether, hexanes,pentane, heptane, cyclohexane, benzene, toluene, as well as halogenatedsolvents such as chloroform, dichloromethane, carbon tetrachloride,1,2-dichloroethane, or combinations thereof. Other extraction solventsare useful in the present invention.

As used herein, the term “hydrophobic furan product” refers to productsof this present process which contain a furan ring, and are generallyinsoluble with water. Hydrophobic furan products include, but are notlimited to, aliphatic and aromatic esters of 5-methyl-2-furoic acid,aliphatic and aromatic amides of 5-methyl-2-furoic acid, and aliphaticand aromatic thioesters of 5-methyl-2-furoic acid.

As used herein, the term “hydrophilic furan product” refers to productsof this present process which contain a furan ring, and are generallysoluble with water. Hydrophilic furan products include, but are notlimited to, 5-methyl-2-furoic acid.

III. Method for Preparing 5-methyl-2-furoic Acid and Derivatives.

The method of the present invention involves preparing furan-containingmolecules of formula I, which are useful chemical building blocks andfuel or fuel additives, from furan-containing molecules of formula II,in greater than 50% yield. The first step involves contacting afuran-containing molecule of formula II, a base, such as DBU, an organicsolvent, such as tetrahydrofuran (THE), a catalyst, such as anN-heterocyclic carbene, and a reactive nucleophile, such as alcohols,water, amines or thiols, in a reaction vessel at a temperature of fromabout −78 degree C. to 150 degree C. After completion, the second stepinvolves separating the product molecules of formula I by extractionwith a hydrophobic solvent, such as ethyl acetate. The yield to methyl5-methyl-2-furoate and ethyl 5-methyl-2-furoate are greater than 70% bythis method.

Useful products for the present invention include molecules of formulaI, wherein R of formula I comprises oxygen, sulfur, and nitrogen; andwherein R′ of formula I comprises carbon, hydrogen, sulfur, nitrogen,oxygen, or any aromatic or aliphatic combination thereof.

In some embodiments, the present invention provides a method forpreparing 5-methyl-2-furoic acid. The method involves contactingfuran-containing molecule of formula II, a base, an organic solvent, acatalyst, and water, in a reaction vessel at a temperature of from about−78 degree C. to 150 degree C.

In some embodiments, the present invention provides a method forpreparing esters of 5-methyl-2-furoic acid. The method involvescontacting furan-containing molecule of formula II, a base, an organicsolvent, a catalyst, and an alcohol, such as methanol, ethanol,propanol, butanol, or other aliphatic or aromatic alcohol, in a reactionvessel at a temperature of from about −78 degree C. to 150 degree C.

In some embodiments, the present invention provides a method forpreparing 5-methylfuran-2-carboxamide, or a substituted amide thereof.The method involves contacting furan-containing molecule of formula II,a base, an organic solvent, a catalyst, and an amine, such as ammonia,an aliphatic or aromatic alkylamine, or an aliphatic or aromaticdialkylamine, in a reaction vessel at a temperature of from about −78degree C. to 150 degree C.

In some embodiments, the present invention provides a method forpreparing 5-methylfuran-2-carbothioic S-acid, or an aliphatic oraromatic thioester thereof. The method involves contactingfuran-containing molecule of formula II, a base, an organic solvent, acatalyst, and a thiol, such as hydrogen sulfide, or an aliphatic oraromatic thiol, in a reaction vessel at a temperature of from about −78degree C. to 150 degree C.

The CMF used in the present invention comprises the exact molecularstructure, “5-(chloromethyl)-2-furaldehyde”, C6H5CIO2. CMF can beproduced from carbohydrate-containing materials, such as agricultural,municipal or forestry waste streams. CMF can also be producedsynthetically, from 5-methyl-2-furaldehyde,5-(hydroxymethyl)-2-furaldehyde, or other furan derivatives throughreactions known to those skilled in the art of organic synthesis.

Useful substrates for the present invention include molecules of formulaII, including CMF, as well as other derivatives of5-methyl-2-furaldehyde, wherein R″ of formula II comprises chloride,fluoride, bromide, iodide, p-toluenesulfonate, methanesulfonate,trifluoroacetate, phenoxy, hydroxy, ammonium, or other atoms or groupingof elements known to participate in this chemistry.

The catalyst used in the present invention comprises those atoms orgroupings of atoms that are known to affect umpulong reactivity inaldehydes. For example, N-heterocyclic carbenes that contain anypolycyclic or heterocyclic organic molecules containing one nitrogenatom, and at least one from the following: nitrogen, sulfur, phosphorus,or silicon; as well as at least one carbon atom. These atoms arearranged in such a way that upon treatment with an anhydrous base, adivalent carbon will form. Such examples include organic or inorganicsalts of thiazolium, 1,2,4-triazolium, imidazolium, and tetrazolium ringsystems, as well as other systems know to generate singlet carbenes.Still other useful catalysts include nucleophilic anion groups such ascyanide, chloride, bromide, and iodide.

The method of the present invention can be carried out at any suitabletemperature. The temperature can be from −78 degree C. to 120 degree C.Other useful ranges for the temperature include from about 10 degree C.to about 50 degree C. Still other useful ranges for the temperatureinclude from about 25 degree C. to about 35 degree C. One of skill inthe art will appreciate that other temperature ranges are useful in thepresent invention.

Methods according to the present invention can be carried out over anysuitable time duration. A useful time duration can be from 1 second to24 hours. Other useful ranges include from about 1 hour to 4 hours. Oneof skill in the art will appreciate that other time durations are usefulin the present invention.

An organic solvent used in the present invention comprises solventswhich are miscible or immiscible with water. Organic solvents include,but are not limited to, tetrahydrofuran, acetonitrile, diethyl ether,methyl t-butyl ether, ethyl acetate, pentane, hexane, heptane,cyclohexane, benzene, toluene, methanol, ethanol, as well as halogenatedsolvents such as chloroform, dichloromethane, carbon tetrachloride,1,2-dichloroethane, or combinations thereof. Other organic solvents areuseful in the present invention.

A hydrophobic solvent in the present invention comprises a solvent thatis immiscible with water. Extraction solvents include, but are notlimited to, diethyl ether, ethyl acetate, methyl t-butyl ether, hexanes,pentane, heptane, cyclohexane, benzene, toluene, as well as halogenatedsolvents such as chloroform, dichloromethane, carbon tetrachloride,1,2-dichloroethane, or combinations thereof. Other hydrophobic solventsare useful in the present invention.

A base used in the present invention can comprise an inorganic base. Forexample, the cation of the base can be an alkali metal, an alkalineearth metal, a transition metal, a post-transition metal, a lanthanideor an actinide. Alkali metals include Li, Na, K, Rb and Cs. Alkalineearth metals include Be, Mg, Ca, Sr and Ba. Transition metals includeSc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd,Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg and Ac. The anion of thebase can be carbonate, hydroxide, phosphate, sulfate, boronate, oracetate.

A base used in the present invention can also comprise anitrogen-containing organic molecule. For example, any sp3 or sp2hybridized amine, such as those contained in pyridine, triethylamine,diisopropylethylamine, trimethylamine, tripropylamine, tributylamine,N,N-dimethylaminopyridine, imidazole, or polycyclic amines, such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), quinuclidine, quinoline, 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), or other related bases.

A base can be present in any useful concentration in the presentinvention. For example, it can occur from super-stoichiometricquantities with respect to the moles of CMF, up to equimolar orsub-stoichiometric quantities.

A method of the present invention can also include other components andreagents known to one of skill in the art. For example, other componentsand reagents can include buffers, surfactants, additional salts, andadditional solvents.

IV. Examples: Ethyl 5-methyl-2-furoate.

1,3-dimesityl-1H-imidazol-3-ium iodide (0.031 g, 0.138 mmol) wassuspended in tetrahydrofuran (46 ml) and ethanol (16.2 ml).1,8-diazabicyclo[5.4.0]undec-7-ene (4.14 ml, 27.68 mmol) was then addedand the reaction heated to 32° C. CMF (2.00 g, 13.84 mmol) was dissolvedin THF (8 ml), and added dropwise over the course of 60 minutes.Stirring was continued for an additional 2 hours, during which time thereaction took on a deep red color. Water (100 ml) was then added, andthe reaction extracted with ethyl acetate (3×150 ml). The combinedorganic extracts were pooled and washed with brine. Desiccation overNa₂SO₄ and solvent evacuation preceded silica chromatography of theresidue (15% Ethyl Acetate:Hexanes), which furnished the ester as a paleyellow oil (1.56 g, 73% yield): 1HNMR δ(CDCl3): 7.04 (d, 1H, J=3 Hz),6.07 (d, 1H, J=3 Hz), 4.31 (q, 1H, J=7 Hz), 2.34 (s, 3H), 1.33 (t, 2H,J=7 Hz); 13CNMR δ(CDCl3): 158.79, 156.97, 143.18, 119.13, 108.29, 60.60,14.29, 13.89.

Other Embodiments

Glycerol is a three-carbon poly-hydroxylated organic molecule that isproduced in abundance by all living organisms. It serves as the backbonefor triacylglycerides, which are the primary source of cellular energyderived from fats, as well as for phospholipids, which comprise thelipid bilayer of cellular membranes. Glycerol's low toxicity andinherent “sweet” taste has seen its inclusion into low calorie foods asa glucose substitute. As a three-carbon, prochiral synthon, glycerol hasbeen utilized as a starting material for many pharmaceutical compounds,as well as academic chemical methodologies. In recent years, theworldwide supply of glycerol has increased dramatically as the demandfor biodiesel fuel rises, and it is projected that 1.2 million tons ofglycerol will be generated in 2010. See, e.g., Ott, L. Bicker, M.;Vogel, H. Green Chem. 2006, 8, 214, which is incorporated herein byreference. Triacylglycerols (triglycerides) are typically harvested fromplant and algal material, then transesterified with short aliphaticalcohols to liberate the fatty acids from the glycerol core. These fattyester products display ideal diesel fuel characteristics, however due toits high water solubility and poor flammability, glycerol is seen as anunwanted by-product in this industry.

A number of chemical methods for the conversion of glycerol to commoditychemicals have been examined. Many involve the further oxidation ofglycerol to acrylate derivatives, which have found use in the polymerindustry. The reduction of glycerol to 1,2- or 1,3-propanediol can beaccomplished using various platinum group metals and hydrogen gas atelevated temperatures (see FIG. 5). One particular method involves thecatalytic dehydration of glycerol to acrolein. See, e.g., Katryniok, B.;Paul, S.; Capron, M.; Dumeignil, F. ChemSusChem, 2009, 2, 719-730, whichis incorporated herein by reference. While not a potential fuel itself,this process is capable of removing two oxygens from glycerol throughnon-hydrogenative conditions, and it is our supposition that acroleincan be combined with other short-chain molecules to generate fuels orchemicals of interest.

Chemically, acrolein contains an aldehyde group and an alkene group. Assuch, acrolein is highly electrophilic and prone to polymerization, soit is used quickly after generation from glycerol. Limiting the acroleinpolymerization to controlled dimerization and trimerization can affordsix-carbon and nine-carbon molecules, respectively, which contain lowoxygen to carbon ratios, and can fall into the proper fuelspecifications for transportation or aviation fuel. Example embodimentsof the present invention provide a method for generating a dimerizedproduct of acrolein through the use of N-heterocyclic carbene (NHC)catalysis.

NHC catalysts take advantage of unusual chemical behaviors of carbenes,which have been known to impart inverted reactivity on certainsubstrates, i.e., “umpulong” reactivity, such as nucleophilic acylgroups. See, e.g, Seebach, D. Angew. Chem. Int. Ed. 1979, 18, 239-258,which is incorporated herein by reference; Breslow, R. J. Am. Chem. Soc.1958, 80, 3719-3726, which is incorporated herein by reference.So-called “persistent” carbenes are encountered in nature in the form ofvitamin B1, thiamine, which is involved in pyruvate decarboxylation andthe subsequent use of the chemical intermediate in cellular metabolism.Recent work by Rovis, Bode, and Scheidt has expanded the scope of thiscatalyst to include a multitude of α-oxoacids and aldehydes in reactionsthat otherwise could not occur under conventional catalysis. See, e.g.,Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004,126, 9518-9519, which is incorporated herein by reference; Chan, A.;Scheidt, K. A. Org. Lett. 2005, 7, 905-908, which is incorporated hereinby reference; Chow, K. Y.-K.; Bode, J. J. Am. Chem. Soc. 2004, 126,8126-8127, which is incorporated herein by reference. Under basicconditions, the thiazolium, imidazolium, or triazolium ring systems actas nucleophilic agents, and will attack electron-deficient carbonylcenters (see FIG. 6). After proton transfer, the acyl carbon center hasin turn become nucleophilic and will attack nearby electrophiles, ortransfer these electrons to an internal, proximal nucleofuge andeffectively create an “internal redox”.

As contemplated in the present invention, two molecules of acrolein canafford the 5-vinylbutyrolactone product shown in FIG. 7, through a NHCcascade reaction, using vitamine B1, or other heterocyclic moietycapable of similar catalysis. Glorius and Bode have shown atransformation of a similar type, wherein a putative homoenolate of anenal can be generated via NHC catalysis, followed by intermolecularattack onto an aldehyde, followed by ring closure and expulsion ofcatalyst. See, e.g., Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem.Soc. 2004, 126, 14370-14371, which is incorporated herein by reference;Burstein, C.; Glorius, F. Angew. Chem. Int. Ed. 2004, 43, 6205-6208,which is incorporated herein by reference.

In this intermediate is contained an allylic acetate, which will besusceptible to Pd(II)Cl₂ insertion. Rearrangement to the -lactone ishighly disfavored entropically, so β-hydride elimination will occurfollowed by olefin isomerization to afford sorbic acid, a six-carboncommodity chemical, which is widely used in the food industry as apreservative. Esterification of sorbic acid with methanol or ethanolunder acid catalysis will generate methyl sorbate and ethyl sorbate,respectively, which display similar melting points and flash points toaviation fuels (flash point: 63° C. and 69° C., respectively; meltingpoint: −46° C. and −34° C., respectively). Hydrogenation of thesecompounds will provide methyl and ethyl hexanoate derivatives, whichshow even lower values for the above fuel categories (flash point: 45°C. and 49° C., respectively; melting point: −71° C. and −67° C.,respectively). FIG. 8 is a schematic illustration of the above process.

An example embodiment according to the present invention provides amethod for the conversion of glycerol to a liquid fuel comprising:catalytic dehydration of glycerol to acrolein; controlled condensationof acrolein to 5-vinylbutyrolactone; conversion of 5-vinylbutyrolactoneto sorbic acid; esterification of sorbic acid to a sorbate ester; andhydrogenation of the sorbate ester to a hexanoate ester. In such amethod, the catalytic dehydration of glycerol to acrolein can comprisereaction with one or more of potassium bisulfate, sulfuric acid,phosphoric acid, magnesium sulfate, zinc sulfate or aluminum sulfate. Insuch a method, the catalytic dehydration of glycerol to acrolein can beperformed at temperatures between 473 kelvin and 673 kelvin, and can beperformed in batch processes and in continuous processes or combinationsthereof.

The controlled condensation of acrolein to 5-vinylbutyrolactone cancomprise reaction with catalytic systems that affect inverted reactivityon acyl groups, such that they become nucleophilic. In such anembodiment, the catalytic systems can comprise one or more ofthiazolium, triazolium, or imidazolium ring systems.

The conversion of 5-vinylbutyrolactone to sorbic acid can compriseisomerization by palladium. The esterification of sorbic acid to asorbate ester can comprises acid catalyzed esterification with analcohol. The esterification of sorbic acid to a sorbate ester cancomprise conversion of the acid to an acid chloride or mixed anhydrideor carbonate and reaction with an alcohol. The esterification of sorbicacid to a sorbate ester can comprise activation of the acid by acarbodiimide coupling agent or other dehydrating reagent and reactionwith an alcohol. The hydrogenation of a sorbate ester to a hexanoateester can comprise reduction by a noble metal, such as palladium,platinum, rhodium, iridium, nickel, iron, or ruthenium, under elevatedpressures of hydrogen gas.

Example embodiments of the present invention comprise liquid fuelsproduced by any of the methods described herein. Example embodiments ofthe present invention comprise apparatuses for the performance of any ofthe methods described herein.

Other Embodiments

The catalytic deoxygenation of cellulosic material is a significanthurdle in the development of cost-effective energy dense liquid fuels.The direct reduction of a carbon-hydroxyl bond is heavily disfavoredthermodynamically, and current state-of-the-art technologies for doingso involve high temperatures, high pressures of hydrogen gas, as well asa platinum-group metal catalyst system for group activation. Nature hascircumvented this problem by capping these hydroxyls as phosphategroups, followed by elimination to provide the olefin. There arenumerous deoxygenation protocols in the organic synthesis literature,though none of these will be compatible in an aqueous environment, norwill they be free of by-products, of which many can be of highermolecular weight than the starting glucose molecule.

Recent reports by Zhang and Raines have shown that cellulosic materialcan be dehydrated through several steps to form furan-based products.See, e.g., Su, Y.; Brown, H. M.; Huang, W.; Zhou, X.-d.; Amonette, J.E.; Zhang, C. “Single-step Conversion of Cellulose to5-hydroxymethylfurfural (HMF), a Versatile Platform Chemical.” App. Cat.A: General. 2009, 361, 117-122, incorporated herein by reference;Binder, J. B.; Raines, R. T. “Simple Chemical Transformation ofLignocellulosic Biomass into Furanics for Fuels and Chemicals.” J. Am.Chem. Soc. 2009, 131, 1979-1985, incorporated herein by reference. Smallscale reactions have shown that glucose can be converted to fructoseusing chromium catalysis in a dry ionic liquid solvent, followed bydehydration to hydroxymethylfurfural (HMF). This reaction proceeds ingood overall yield, however the reaction conditions are not amenable tolarge scale production.

A report by Mascal has addressed these issues and developed an acidcatalyzed procedure for the production of 5-(chloromethyl)furfural (CMF)from cellulose directly. See, e.g., Mascal, M.; Nikitin, E. B.; “Direct,High-Yield Conversion of Cellulose into Biofuel.” Angew. Chem. Int. Ed.2008, 47, 7924-7926, incorporated herein by reference. Using acid, heat,lithium chloride, and a biphasic reaction setup, hydrophobic CMF can becontinuously extracted from the reaction medium and then utilized forsubsequent etherification or condensation reactions.

The present invention provides a novel chemical transformation on CMF,involving an oxidative coupling reaction to generate furoate esterswhich may serve as “drop-in” gasoline or diesel fuel surrogates.

α-chloroaldehydes have been shown to undergo an internaloxidation-reduction reaction to generate ester products when treatedwith thiamine-like (Vitamin B1) molecules. See, e.g., Reynolds, N. T.;de Alaniz, J. R.; Rovis, T. “Conversion of a-haloaldehydes into acyatingagents by an internal redox reaction catalyzed by nucleophiliccarbenes.” J. Am. Chem. Soc. 2004, 126, 9518-9519, incorporated hereinby reference. CMF does not contain a α-chloroaldehyde per se; howeverthe aromatic connection between the aldehyde and chloromethyl linksthese groups through conjugative effects, and can therefore be thoughtof as a “doubly-vinylogous or phenylic” α-chloroaldehyde. There havebeen no reports of a reaction of this kind.

FIG. 9 illustrates schematically chloroaldehyde attacked by thethiazolium ring, followed by elimination of the chloride.Tautomerization to the ketone provides an intermediate which issusceptible to hydrolysis by water or esterification by an alcohol.

To facilitate catalyst recovery, thiazolium of triazolium hetereocyclecan be attached to a solid support or supramolecular construct, such asa calixarene or cyclodextrin molecule. Breslow has shown that thiazoliumsalts covalently anchored to γ-cyclodextrin operate nine times fasterthan their free counterparts in the analogous benzoin condensation.Breslow, R.; Kool, E. “A γ-Cyclodextrin Thiazolium Salt Holoenzyme Mimicfor the Benzoin Condensation.” Tetrahedron Lett. 1988, 29, 1635-1638,incorporated herein by reference.

An example embodiment according to the present invention provides amethod for the conversion of 5-(chloromethyl)furfural to a liquid fuelcomprising: nucleophilic addition of a carbene catalyst to the aldehydeof 5-(chloromethyl)furfural and loss of chloride ion; displacement ofthe carbene catalyst with an alcohol. In such a method, the carbenecatalyst can comprise a thiazolium, triazolium or imidazoliumheterocycle. In such a method, the reaction solvent can comprise anappropriately buffered aqueous solution, or organic solvent, such asdichloromethane, dimethylformamide, tetrahydrofuran, chloroform,benzene, toluene, or acetonitrile.

The displacement of the carbene catalyst with an alcohol can comprisereaction with any aliphatic or aromatic alcohol, such that a furoateester product is generated.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein isincorporated by reference in its entirety to the same extent as if eachreference was individually incorporated by reference.

We claim:
 1. A method for the synthesis of furan-containing molecules offormula I from furan-containing molecules of formula II, the methodcomprising: (a) contacting a furan-containing molecule of formula II, abase, an organic solvent, a catalyst, and a reactive nucleophile in areaction vessel at a temperature of from about −78 degree C. to about150 degree C., such that furan-containing molecules of formula I areproduced; (b) separating the product molecules of formula I byextraction with a hydrophobic solvent, or else by chromatography,distillation, sublimation, or precipitation.
 2. A method as in claim 1,wherein R of formula I comprises oxygen, sulfur, and nitrogen.
 3. Amethod as in claim 1, wherein R′ of formula I comprises carbon,hydrogen, sulfur, nitrogen, oxygen, or any aromatic or aliphaticcombination thereof;
 4. A method as in claim 1, wherein R″ of formula IIcomprises chloride, fluoride, bromide, iodide, p-toluenesulfonate,methanesulfonate, trifluoroacetate, phenoxy, hydroxy, or ammonium.
 5. Amethod as in claim 1, wherein the base comprises an inorganic base.
 6. Amethod as in claim 1, wherein the base comprises a nitrogen-containingorganic base.
 7. A method as in claim 1, wherein the organic solvent ismiscible with water.
 8. A method as in claim 1, wherein the organicsolvent is immiscible with water.
 9. A method as in claim 1, wherein thecatalyst comprises nucleophilic anion groups consisting of cyanide,chloride, bromide, or iodide.
 10. A method as in claim 1, wherein thecatalyst comprises a N-heterocyclic carbene or salt thereof.
 11. Amethod as in claim 1, wherein the reactive nucleophile comprises water.12. A method as in claim 1, wherein the reactive nucleophile comprisesan alcohol.
 13. A method as in claim 1, wherein the reactive nucleophilecomprises an amine.
 14. A method as in claim 1, wherein the reactivenucleophile comprises a thiol.
 15. A method as in claim 1, wherein thetemperature is from about 25 degrees C. to 35 degrees C.
 16. A method asin claim 1, wherein the hydrophobic solvent comprises a solvent that isimmiscible with water.